Circadian variation in cortisol reactivity to an acute stressor

To investigate the role of the circadian pacemaker in cortisol reactivity to a cold pressor challenge, 26 diurnally subjects participated in a constant-routine protocol and were divided into two groups. Group 1 started immediately after a monitored sleep period at 09:00 h, while group 2 started 12 h later. After 2 h of adaptation, a cold pressor test was presented every 3 h. The cortisol response was assessed by means of saliva samples that were taken before and after the test. The pretest samples were considered to be base-rate measures and base-rate values as subtracted from post-test values were considered as reactivity measures. Both measures showed distinct Time-of-Day variations (respectively: F(7,168) = 16.92, p < 0.001, epsilon = 0.383; and F(7,175) = 8.01, p < 0.001, epsilon = 0.523). These findings are interpreted as evidence for the existence of an endogenous circadian periodicity underlying the sensitivity of the hypothalamus-pituitary-adrenal (HPA)-axis to acute stress.     

Evaluating attention-deficit/hyperactivity disorder using ecological momentary assessment: a systematic review

Ecological momentary assessment is an excellent tool for the measurement of different day-to-day domains in patients and capturing real-world and real-time data. The purpose of this review is to evaluate feasibility in current ecological momentary assessment studies on emotional and behavioral functioning, functional impairments, and quality of life patients with an attention-deficit/hyperactivity disorder diagnosis. This systematic review follows the recommendation of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines selecting articles published from January 1, 1990, up to the latest access on May 2018, identifying a pool of 23 eligible studies. Twenty-three studies demonstrate the validity of ecological momentary assessment methodology in evaluating different aspects of patients with attention-deficit/hyperactivity disorder. Fifteen studies focus on the child’s or adolescent’s daily behavior, while eight studies only focus on adults. The studies presented in this review monitored patients and their families over a maximum period of 28 days. We can conclude that ecological momentary assessment can be successfully implemented with attention-deficit/hyperactivity disorder patients to evaluate diverse backgrounds. However, more studies are needed with a longer monitoring period, especially in adolescents, to determine the effectiveness of ecological momentary assessment on patients with attention-deficit/hyperactivity disorder.     

Relationship between atomoxetine plasma concentration, treatment response and tolerability in attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder

The purpose of this study was to examine whether atomoxetine plasma concentration predicts attention-deficit/hyperactivity disorder (ADHD) or oppositional defiant disorder (ODD) response. This post-hoc analysis assessed the relationship between atomoxetine plasma concentration and ADHD and ODD symptoms in patients (with ADHD and comorbid ODD) aged 6–12 years. Patients were randomly assigned to atomoxetine 1.2 mg/kg/day (n = 156) or placebo (n = 70) for 8 weeks (Study Period II). At the end of 8 weeks, ODD non-remitters (score >9 on the SNAP-IV ODD subscale and CGI-I > 2) with atomoxetine plasma concentration <800 ng/ml at 2 weeks were re-randomized to either atomoxetine 1.2 mg/kg/day or 2.4 mg/kg/day for an additional 4 weeks (Study Period III). ODD remitters and non-remitters with plasma atomoxetine ≥800 ng/ml remained on 1.2 mg/kg/day atomoxetine for 4 weeks. Patients who received atomoxetine, completed Study Period II, and entered Study Period III were included in these analyses. All the groups demonstrated improvement on the SNAP-IV ODD and ADHD-combined subscales (P < .001). At the end of Study Periods II and III, ODD and ADHD improvement was significantly greater in the remitter group compared with the non-remitter groups. Symptom improvement was numerically greater in the non-remitter (2.4 mg/kg/day compared with the non-remitter 1.2 mg/kg/day) group. Atomoxetine plasma concentration was not indicative of ODD and ADHD improvement after 12 weeks of treatment. ADHD and ODD symptoms improved in all the groups with longer duration on atomoxetine. Results suggest atomoxetine plasma concentration does not predict ODD and ADHD symptom improvement. However, a higher atomoxetine dose may benefit some patients.     

Differentiation between attention-deficit/hyperactivity disorder and autism spectrum disorder by the Social Communication Questionnaire

The differentiation of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) poses a clinical challenge. In children, overlap of psychopathological and cognitive findings has been found for both disorders. In addition, some children suffer from both disorders. The Social Communication Questionnaire (SCQ) is a screening instrument for ASD symptoms which indicates the presence of ASD in a rapid and economic way. However, validity to differentiate ASD and ADHD as differential or comorbid diagnoses has not been studied. Here, the differential validity was compared in groups of children with ASD, ADHD, ASD + ADHD, and typically developing (TD) children and IQ > 70. ROC analyses indicated an excellent differentiation between ASD and TD with ROC–AUC = .941 and between ASD + ADHD with ROC–AUC = .993. The optimal cutoff was below the originally recommended one of 15. The differentiation between children with ASD with (ROC–AUC = .982) or without ADHD (ROC–AUC = .864) and ADHD alone also showed acceptable differential validity, and here, the optimal cutoff corresponded to the recommended. Taken together, the SCQ can be recommended as a screening instrument for a first differentiation between children with ASD and typically developing children as well as children with ADHD.     

Effects of interpersonal violence-related post-traumatic stress disorder (PTSD) on mother and child diurnal cortisol rhythm and cortisol reactivity to a laboratory stressor involving separation

Women who have experienced interpersonal violence (IPV) are at a higher risk to develop posttraumatic stress disorder (PTSD), with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and impaired social behavior. Previously, we had reported impaired maternal sensitivity and increased difficulty in identifying emotions (i.e. alexithymia) among IPV-PTSD mothers. One of the aims of the present study was to examine maternal IPV-PTSD salivary cortisol levels diurnally and reactive to their child's distress in relation to maternal alexithymia. Given that mother-child interaction during infancy and early childhood has important long-term consequences on the stress response system, toddlers' cortisol levels were assessed during the day and in response to a laboratory stressor. Mothers collected their own and their 12–48 month-old toddlers' salivary samples at home three times: 30 min after waking up, between 2–3 pm and at bedtime. Moreover, mother-child dyads participated in a 120-min laboratory session, consisting of 3 phases: baseline, stress situation (involving mother-child separation and exposure to novelty) and a 60-min regulation phase. Compared to non-PTSD controls, IPV-PTSD mothers — but not their toddlers, had lower morning cortisol and higher bedtime cortisol levels. As expected, IPV-PTSD mothers and their children showed blunted cortisol reactivity to the laboratory stressor. Maternal cortisol levels were negatively correlated to difficulty in identifying emotions. Our data highlights PTSD-IPV-related alterations in the HPA system and its relevance to maternal behavior. Toddlers of IPV-PTSD mothers also showed an altered pattern of cortisol reactivity to stress that potentially may predispose them to later psychological disorders.     

Relationship between attention-deficit/hyperactivity disorder and sedentary behavior in adolescence: a cross-sectional study

Existing studies reveal that high levels of sedentary behavior are associated with more inattention and hyperactivity problems. Since most previous studies used screen time as an indicator of sedentary behavior and assessed symptoms of attention-deficit/hyperactivity disorder (ADHD) by short screening measures which do not allow to distinguish between subtypes of ADHD, the current study aimed to investigate association between different types of sedentary behavior and symptoms and subtypes of ADHD. The current cross-sectional study analyzed data of 913 students (46.1% girls) aged 13–17 years (M = 15.0, SD = 0.6). Using a self-administered questionnaire, screen-based and non-screen-based sedentary behavior and ADHD symptoms were assessed. Linear and logistic regression analyses were conducted. All analyses were adjusted for age, gender, moderate to vigorous physical activity and body mass index. Screen time was related to the total ADHD score (p < 0.001) as well as to the subscales inattention (p ≤ 0.016) and hyperactivity/impulsivity (p ≤ 0.008). Sedentary time without screens was virtually not associated with ADHD. As far as ADHD symptoms are considered as a correlate of sedentary behavior, the type of activity which is pursued sedentarily seems to matter: screen time, but not other non-screen-based sedentary activities should be considered as being a risk factor for ADHD.     

Diagnosing and treating attention-deficit/hyperactivity disorder in adults

Adult attention deficit/hyperactivity disorder (ADHD) is a valid and impairing psychiatric disorder. In this article, we review the diagnosis of ADHD in adults, focusing on symptom presentation differences between pediatric and adult ADHD as well as the importance of assessing functional impairments. Differentiating ADHD from other clinical disorders is often the most difficult part of making an ADHD diagnosis in adults. Psychiatric comorbidities are also described and discussed as potential impact factors upon not only diagnosing ADHD but also treatment of adult ADHD. Especially in those adults with psychiatric comorbidities, treatments need to be multimodal and include both pharmacotherapy and psychosocial interventions.     

Executive functioning in attention-deficit/hyperactivity disorder: questioning the notion of planning deficits with heart rate reactivity

This study employed a paired stimulus paradigm to compare phasic changes in heart rate among children (age categories 6–8, 9–10, and 11–12) and adults (age categories 18–19 and 20–22) with attention-deficit/hyperactivity disorder (ADHD) and age-matched controls. A sample of 95 participants (19 ADHD-diagnosed children, 34 controls, 20 ADHD-diagnosed adults, and 22 controls) solved a planning task, the Tower of London, through 4 levels of difficulty. It was hypothesized that groups with ADHD would show greater heart rate acceleration and less final deceleration than would controls, and that these heart rate responses would change with age and difficulty level as well. Though heart rate differences were found among age categories and difficulty levels, none were found between participants with ADHD and controls. The lack of ADHD differences are not consistent with the behavioral evidence that planning by itself is one of the marked executive function deficits in ADHD. Because ADHD differences were not evident, the effects either were not present or were smaller than that of difficulty level and age. Possible explanations for this lack of difference and future directions are discussed.     

A genomewide scan for loci involved in attention-deficit/hyperactivity disorder

Attention deficit/hyperactivity disorder (ADHD) is a common heritable disorder with a childhood onset. Molecular genetic studies of ADHD have previously focused on examining the roles of specific candidate genes, primarily those involved in dopaminergic pathways. We have performed the first systematic genomewide linkage scan for loci influencing ADHD in 126 affected sib pairs, using a approximately 10-cM grid of microsatellite markers. Allele-sharing linkage methods enabled us to exclude any loci with a lambda(s) of > or =3 from 96% of the genome and those with a lambda(s) of > or =2.5 from 91%, indicating that there is unlikely to be a major gene involved in ADHD susceptibility in our sample. Under a strict diagnostic scheme we could exclude all screened regions of the X chromosome for a locus-specific lambda(s) of >/=2 in brother-brother pairs, demonstrating that the excess of affected males with ADHD is probably not attributable to a major X-linked effect. Qualitative trait maximum LOD score analyses pointed to a number of chromosomal sites that may contain genetic risk factors of moderate effect. None exceeded genomewide significance thresholds, but LOD scores were >1.5 for regions on 5p12, 10q26, 12q23, and 16p13. Quantitative-trait analysis of ADHD symptom counts implicated a region on 12p13 (maximum LOD 2.6) that also yielded a LOD >1 when qualitative methods were used. A survey of regions containing 36 genes that have been proposed as candidates for ADHD indicated that 29 of these genes, including DRD4 and DAT1, could be excluded for a lambda(s) of 2. Only three of the candidates-DRD5, 5HTT, and CALCYON-coincided with sites of positive linkage identified by our screen. Two of the regions highlighted in the present study, 2q24 and 16p13, coincided with the top linkage peaks reported by a recent genome-scan study of autistic sib pairs.     

Neurocognitive correlates of adult attention-deficit/hyperactivity disorder in a Turkish sample

We established a neuropsychological testing profile among Turkish adults presenting with ADHD controlling for general intelligence and comorbid psychiatric conditions. Adults with ADHD frequently present with comorbid conditions (e.g., mood and substance use/abuse disorders) that may have a detrimental impact on neurocognitive function. Hence, we excluded patients with ADHD meeting criteria for comorbid psychiatric syndromes. A comprehensive neuropsychological test battery was administered to adults with ADHD attending a general psychiatry clinic in Istanbul, Turkey, and healthy control participants. Adults with ADHD demonstrated performance deficits on tests of attention, information processing speed, and general and working memory. Patients with ADHD also reported a significantly greater number of symptoms associated with frontal lobe syndromes (i.e., dysexecutive symptoms and disinhibition). Patients with ADHD demonstrated rather striking deficits on tests of verbal and nonverbal memory. Once information was encoded, however, patients with ADHD do not demonstrate significant information loss. Patients with ADHD and healthy controls did not differ on tests of alternation learning, inhibitory control (error rates), and ToM skills. Findings support the contention that dorsal-prefrontal (rather than ventral-prefrontal) dysfunction is associated with adult ADHD. Unexpectedly, groups did not differ on executive control and fluency tasks. Yet patients with ADHD obtained substantially higher scores on a self-report measure of executive dysfunction. This suggests that dysexecutive symptoms among patients with ADHD in the current study do not reflect set-shifting or organizational deficits. Rather, symptoms may reflect attentional and working memory deficits as well as diminished information processing speed.     

Trace elements in drinking water and the incidence of attention-deficit hyperactivity disorder

BackgroundTrace elements have been suggested to have neurotoxic effects and increase the risk of neurodevelopmental disorders, but studies of a potential role of trace elements in relation to Attention-Deficit/Hyperactivity Disorder (ADHD) are very limited. The objective of this study was to conduct an exploratory analysis investigating the associations between 17 geogenic trace elements (Ba, Co, Eu, I, Li, Mo, Rb, Re, Rh, Sb, Sc, Se, Si, Sr, Ti, U and Y) found in Danish drinking water and the risk of developing ADHD.MethodsIn this cohort study, 284,309 individuals, born 1994–2007, were followed for incidence of ADHD from the age of five until the end of study, December 31, 2016. We conducted survival analyses, using Poisson regression to estimate incidence rate ratios (IRRs) with 95 % confidence intervals (CI) in three different confounder adjustment scenarios.ResultsIn a model including adjustments for age, sex, calendar year, parental socio-economic status, neighborhood level socio-economic status and parental psychiatric illness, we found that six of the 17 trace elements (Sr, Rb, Rh, Ti, Sb and Re) were associated with an increased risk of ADHD, whereas two (Ba and I) were inversely associated with ADHD. However, when including region as a covariate in the model, most trace elements were no longer associated with ADHD or the association changed direction. Four trace elements (I, Li, Rb, and Y) remained significantly associated with ADHD but in an inverse direction and for three of these (I, Li and Y), we found significant interactions with region in their association with ADHD.ConclusionThe trace elements under investigation, at levels found in Danish drinking water, do not seem to contribute to the development of ADHD and our findings highlight the importance of examining consistency of associations across geographic areas.     

miRNA profiling in the hippocampus of attention-deficit/hyperactivity disorder rats

Attention-deficit/hyperactivity disorder (ADHD) is characterized by attention deficit, hyperactivity, impulsivity, and learning and memory impairment. Although the pathogenesis of learning and memory impairment is still unknown, some studies have suggested an association with hippocampus dysfunction. We aimed to explore the role of miRNAs in the learning and memory impairments observed in ADHD. Differentially expressed hippocampal micro-ribonucleic acids (miRNAs) in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) were detected on an Illumina HiSeq. 2000 genome analyzer. A total of 25 differentially expressed miRNAs (fold-change ≥ 2 and P-value < 0.05) were identified. The target genes of these differentially expressed miRNAs were predicted using online tools (TargetScan and miRDB). Gene ontology and pathway analysis of the predicted target genes were carried out to assess their putative biological functions. Meanwhile, quantitative real-time PCR was used to validate the HiSeq results, revealing that three miRNAs (miR-1-b, miR-741-3p, and miR-206-3p) were upregulated and four (miR-182, miR-471-5p, miR-183-5p, and miR-211-5p) were downregulated in the SHR group compared with the WKY group. In addition, we confirmed that Dyrk1a is regulated by miR-211-5p. These results help us understand the contribution of miRNAs in the hippocampus to ADHD and provide new insights into the pathogenesis of this condition.     

Intolerance of uncertainty in children with attention-deficit/hyperactivity disorder

Intolerance of uncertainty (IU) has often been studied in the context of internalizing disorders, but no studies to our knowledge have explored the relation between IU and externalizing disorders. Given the proposed link between IU and emotion regulation, the current study sought to examine levels of IU in an externalizing clinical population with known emotion regulation difficulties—attention-deficit/hyperactivity disorder (ADHD). IU levels in this population were compared to a clinical population known to experience elevated levels of IU. Participants in present study were ninety-three children (36 anxiety disorder, 28 ADHD, 29 unaffected children) ages 7–13, who completed the Intolerance of Uncertainty Scale—Short Version (IUS). Responses on the IUS were converted to total IU, prospective IU, and inhibitory IU. A linear mixed model analysis of covariance was conducted while controlling for age, sex, and ADHD medications. A significant interaction was observed between diagnostic status and IU scale. Planned contrasts indicated that children with anxiety disorders and ADHD reported significantly higher levels of IU relative to unaffected children, and children with ADHD reported comparable levels of inhibitory IU relative to children with anxiety disorders. The current results contribute to a growing literature on the link between IU and psychopathology. IU appears to be a transdiagnostic construct present among children with internalizing and externalizing disorders, and may be broadly associated with emotion regulation deficits rather than specific disorder symptoms.     

Nutrition in the treatment of attention-deficit hyperactivity disorder: a neglected but important aspect

Attention-deficit hyperactivity disorder (ADHD) is multidetermined and complex, requiring a multifaceted treatment approach. Nutritional management is one aspect that has been relatively neglected to date. Nutritional factors such as food additives, refined sugars, food sensitivities/allergies, and fatty acid deficiencies have all been linked to ADHD. There is increasing evidence that many children with behavioral problems are sensitive to one or more food components that can negatively impact their behavior. Individual response is an important factor for determining the proper approach in treating children with ADHD. In general, diet modification plays a major role in the management of ADHD and should be considered as part of the treatment protocol.     

Efficacy of carnitine in the treatment of children with attention-deficit hyperactivity disorder

To determine safety and the efficacy of carnitine treatment in children with attention-deficit hyperactivity disorder (ADHD). The ADHD behavior was observed by parents completing the Child Behavior Checklist (CBCL) and by teachers completing the Conners teacher-rating score, in a randomized, double-blind, placebo-controlled double-crossover trial. In 13/24 boys receiving carnitine, home behavior improved as assessed with the CBCL total score (P < 0.02). In 13/24 boys, school behavior improved as assessed with the Conners teacher-rating score (P < 0.05). Before treatment, the CBCL total and sub-scores were significantly different from those of normal Dutch boys (P < 0.0001). Responders showed a significant improvement of the CBCL total scores compared to baseline (P < 0.0001). In the majority of boys no side effects were seen. At baseline and after carnitine treatment, responders showed higher levels of plasma-free carnitine (P < 0.03) and acetylcarnitine (P < 0.05). Compared to baseline, the carnitine treatment caused in the responsive patients a decrease of 20-65% (8-48 points) as assessed by the CBCL total problem rating scale. Treatment with carnitine significantly decreased the attention problems and aggressive behavior in boys with ADHD.     

Joint analysis of the DRD5 marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable, heterogeneous disorder of early onset, consisting of a triad of symptoms: inattention, hyperactivity, and impulsivity. The disorder has a significant genetic component, and theories of etiology include abnormalities in the dopaminergic system, with DRD4, DAT1, SNAP25, and DRD5 being implicated as major susceptibility genes. An initial report of association between ADHD and the common 148-bp allele of a microsatellite marker located 18.5 kb from the DRD5 gene has been followed by several studies showing nonsignificant trends toward association with the same allele. To establish the postulated association of the (CA)(n) repeat with ADHD, we collected genotypic information from 14 independent samples of probands and their parents, analyzed them individually and, in the absence of heterogeneity, analyzed them as a joint sample. The joint analysis showed association with the DRD5 locus (P=.00005; odds ratio 1.24; 95% confidence interval 1.12-1.38). This association appears to be confined to the predominantly inattentive and combined clinical subtypes.     

Olfactory and gustatory sensitivity in adults with attention-deficit/hyperactivity disorder

Recently, research on olfactory functions in attention-deficit/hyperactivity disorder (ADHD) has become prominent, whereas gustation has never been investigated. Increased odor sensitivity was found in medication-na?ve children with ADHD, but not in adult ADHD, which might be due to a dopaminergic dysregulation presumed to underlie this disorder. Taste sensitivity, in particular bitter sensitivity as a hereditary trait, also might be altered in ADHD. To examine olfactory and gustatory functions in adult ADHD patients, we assessed odor sensitivity by Sniffin' Sticks, taste sensitivity by taste strips, and bitter sensitivity by the one-solution test in women with ADHD (n = 12), Bulimia Nervosa (n = 12), and healthy control women (n = 12). Bulimia Nervosa as second patient group was included to control for effects of impulsivity. Preliminary results indicate that ADHD patients were significantly more often classified as tasters, i.e. perceived the bitter taste as more intense, compared to both bulimic patients and healthy controls. No group differences were found with regard to general odor and taste sensitivity. It is proposed that the higher frequency of tasters in ADHD patients might underlie a genetic variation of the bitter receptor-dependent signaling pathway associated with ADHD.     

Human plasma glycome in attention-deficit hyperactivity disorder and autism spectrum disorders

Over a half of all proteins are glycosylated, and their proper glycosylation is essential for normal function. Unfortunately, because of structural complexity of nonlinear branched glycans and the absence of genetic template for their synthesis, the knowledge about glycans is lagging significantly behind the knowledge about proteins or DNA. Using a recently developed quantitative high throughput glycan analysis method we quantified components of the plasma N-glycome in 99 children with attention-deficit hyperactivity disorder (ADHD), 81 child and 5 adults with autism spectrum disorder, and a total of 340 matching healthy controls. No changes in plasma glycome were found to associate with autism spectrum disorder, but several highly significant associations were observed with ADHD. Further structural analysis of plasma glycans revealed that ADHD is associated with increased antennary fucosylation of biantennary glycans and decreased levels of some complex glycans with three or four antennas. The design of this study prevented any functional conclusions about the observed associations, but specific differences in glycosylation appears to be strongly associated with ADHD and warrants further studies in this direction.